Background: Xenobiotic metabolism hinges on a delicate balance between phase I (bioactivation) and phase II (detoxification) enzymatic activity. Suppression of bioactivation has been shown to protect against drug-induced liver injury. In humans, cytochrome P4502E 1 (CYP2E1) is suppressed by IFN-( and other mediators of the inflammatory response. A mechanism for this decrease in activity and its role in affording host advantage has not yet been proposed. Preliminary Findings: Based on our preliminary studies of CYP2E1 expression, we now propose a novel mechanism of feedback-regulation. Within the proximal promoter of the human CYP2E1 gene is a nucleotide sequence ((-interferon activation sequence, GAS) responsible for y-interferon ((-IFN)-dependent suppression of gene transcription. A naturally occurring polymorphism, G(-71)T within this sequence renders the CYP2E1-promoter insensitive to suppression by (-IFN. General Hypothesis: Intracellular production of reactive-metabolic intermediates is regulated by a negative feedback mechanism sensitive to the structure of the CYP2E1 promoter. In order to test this hypothesis it is first necessary to demonstrate a viable mechanism. Thus, our Working hypothesis for this proposal is: Interferon-( suppresses CYP2E1 transcription by acting through the GAS element. This mechanism limits the intracellular pool of CYP2E1 enzyme and decreases the production of reactive metabolic intermediates. Polymorphism of the GAS structure prohibits IFN-(-dependent regulation of CYP2E1 and therefore increases risk of toxicity due to accumulation of reactive metabolic intermediates Approach: To test this hypothesis, we will; i) Characterize the molecular mechanisms of IFN-(-mediated suppression of CYP2E1 in humans; ii) Define the influence of IFN-( on the metabolism and toxicity of substrates bioactivated by CYP2E1; iii) Define the clinical significance of the CYP2E1*7B allele in selected human diseases linked to the bioactivity of CYP2E1; and, iv) Demonstrate that control of CYP2E1 expression is linked to inflammation caused by toxic injury in a physiologic model. Significance: This research will identify a novel and perhaps general mechanism to explain variability in susceptibility to human disease resulting from exposure to medicinal and environmental substrates of CYP2E1. These findings may lead to an approach for identifying susceptible individuals and provide insight into potential therapeutic or preventive strategies. [unreadable] [unreadable]